U.S. Pat. Nos. 3,238,212, 3,067,203 and 3,217,007 (incorporated herein by reference) describe isoquinoline derivatives and their salts as possessing analgesic, spasmolytic and antitussive activities. Mol. Pharmacol. (1976), 12(5), 854-61 describes tests of tetrahydroisoquinolines for agonist and antagonist activity with dopamine and beta adenylate cyclase system.
NMDA receptors have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS as well as learning and memory formation. Under pathological conditions of acute and chronic forms of neurodegeneration overactivation of NMDA receptors is a key event for triggering neuronal cell death.
NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors, displaying different pharmacological properties.
Therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused for example by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic laterial sclerosis) and neurodegeneration associated with bacterial or viral infections, and, in addition, therapeutic indications such as schizophrenia, anxiety and depression.